SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling

Yue Xu, Haifeng Zhang, Yuxin Chen, Jordan S. Pober, Min Zhou (), Jenny Huanjiao Zhou () and Wang Min ()
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Yue Xu: Yale University School of Medicine
Haifeng Zhang: Yale University School of Medicine
Yuxin Chen: The Affiliated Hospital of Nanjing University Medical School
Jordan S. Pober: Yale University School of Medicine
Min Zhou: The Affiliated Hospital of Nanjing University Medical School
Jenny Huanjiao Zhou: Yale University School of Medicine
Wang Min: The Affiliated Hospital of Nanjing University Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Serum response factor (SRF) controls gene transcription in vascular smooth muscle cells (VSMCs) and regulates VSMC phenotypic switch from a contractile to a synthetic state, which plays a key role in the pathogenesis of cardiovascular diseases (CVD). It is not known how post-translational SUMOylation regulates the SRF activity in CVD. Here we show that Senp1 deficiency in VSMCs increased SUMOylated SRF and the SRF-ELK complex, leading to augmented vascular remodeling and neointimal formation in mice. Mechanistically, SENP1 deficiency in VSMCs increases SRF SUMOylation at lysine 143, reducing SRF lysosomal localization concomitant with increased nuclear accumulation and switching a contractile phenotype-responsive SRF-myocardin complex to a synthetic phenotype-responsive SRF-ELK1 complex. SUMOylated SRF and phospho-ELK1 are increased in VSMCs from coronary arteries of CVD patients. Importantly, ELK inhibitor AZD6244 prevents the shift from SRF-myocardin to SRF-ELK complex, attenuating VSMC synthetic phenotypes and neointimal formation in Senp1-deficient mice. Therefore, targeting the SRF complex may have a therapeutic potential for the treatment of CVD.

Date: 2024
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DOI: 10.1038/s41467-024-51350-5

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